Project Summary/Abstract The Tumor Microenvironment Program at USC Norris was created in 2003. The concept behind this Program is that the fundamental investigation of the mechanisms that control the interaction between malignant cells and their nontransformed microenvironment should lead to the identification of novel targets for therapeutic intervention and better prognosticators. The overarching goal is to make innovative basic discoveries on the role of the tumor microenvironment (TME), and by interacting with other Programs of USC Norris, develop these discoveries into investigator-driven clinical trials. The Program has three scientific objectives: 1) to investigate the fundamental mechanisms of communication between cancer cells and their microenvironment; 2) to understand the contribution of viral-induced lymphangiogenesis/angiogenesis to Kaposi sarcoma; and 3) to understand the mechanisms of immune escape and develop new approaches to cancer immunotherapy. The Program Co-Leaders Yves DeClerck and Martin Kast have complementary recognized expertise in the tumor microenvironment and in immunotherapy, respectively. The Program brings together 28 members from 16 departments in four schools at USC with expertise and research interests in inflammation, tumor-stroma interaction, metastasis, angiogenesis, Kaposi sarcoma-associated Herpes Virus (KSHV), human papilloma virus (HPV)-mediated oncogenesis, and immunotherapy. The Program has obtained new funding in the tumor microenvironment (one U54, three R01s, one DoD) and in viral-mediated angiogenesis/lymphangiogenesis (one P01 and one R21). A unique aspect of this basic science program has been its commitment to translation. Over the last five years, the Program has been the hub where fundamental observations made by its members have led to nine clinical studies/trials. Research conducted by members of the Program has a unique impact on specific populations of the LA County catchment area, particularly children (neuroblastoma and childhood ALL), women of low economic status (HPV-induced cervical cancer), and HIV-infected patients (Kaposi sarcoma). During the current project period, Program members have published 319 papers, of which 40% are inter-programmatic, 17% are intra-programmatic, and 28% inter-institutional. Program members have $11M (direct costs) in peer-review funding, with 40% from NCI and 27% from other NIH sources, and 5% from other peer-reviewed sources.